This invention relates to a group of biphenyl sulfonamide compounds and derivatives which inhibit matrix metalloproteinase enzymes and thus are useful for treating diseases resulting from connective tissue breakdown, such as heart disease, multiple sclerosis, arthritis, atherosclerosis, and osteoporosis.
Matrix metalloproteinases (sometimes referred to as MMPs) are naturally-occurring enzymes found in most mammals. Over-expression and activation of MMPs or an imbalance between MMPs and inhibitors of MMPs have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues.
Stromelysin-1 and gelatinase A are members of the matrix metalloproteinases (MMP) family. Other members include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), gelatinase B (92 kDa gelatinase) (MMP-9), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), matrilysin (MMP-7), collagenase 3 (MMP-13), TNF-alpha converting enzyme (TACE), and other newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature, 1994;370:61-65). These enzymes have been implicated with a number of diseases which result from breakdown of connective tissue, including such diseases as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation which leads to restenosis and ischemic heart failure, and tumor metastasis. A method for preventing and treating these and other diseases is now recognized to be by inhibiting metalloproteinase enzymes, thereby curtailing and/or eliminating the breakdown of connective tissues that results in the disease states.
The catalytic zinc in matrix metalloproteinases is typically the focal point for inhibitor design. The modification of substrates by introducing zinc chelating groups has generated potent inhibitors such as peptide hydroxamates and thiol-containing peptides. Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat animal models of cancer and inflammation. MMP inhibitors have also been used to prevent and treat congestive heart failure and other cardiovascular diseases, U.S. Pat. No. 5,948,780.
There is a need to discover new low molecular weight compounds that are potent inhibitors of MMP enzymes without causing undesired side effects in animals. McClure recently described a series of arylsulfonyl hydroxamic acid derivatives that are said to be useful as broad spectrum MMP inhibitors (see WO 98/34918). We now have discovered a series of biphenyl sulfonamides that are especially potent MMP inhibitors with little or no toxic effects.
In a preferred embodiment, this invention provides a group of cyclic sulfonamide compounds that are inhibitors of matrix metalloproteinase enzymes, and especially MMP-2, -3, -9, -12, -13, and -14. The invention is more particularly directed to compounds defined by Formula I 
Or a pharmaceutically acceptable salt thereof,
wherein:
Each R1 and R2 independently are hydrogen or C1-C6 alkyl;
Z is (CH2)n;
each R3 and R4 independently are hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; (CH2)m OH, (CH2)m OR5, (CH2)m cycloalkyl, (CH2)m aryl, (CH2)m substituted aryl, (CH2)m heteroaryl, (CH2)m substituted heteroaryl, (CH2)m carbocycle, (CH2)m heterocycle; (CH2)m NR5R6, (CH2)m COR5, (CH2)m CONR5R6, or (CH2)m CO2R5, NO2, phenoxy, CN, CHO;
or two R3 groups on adjacent carbon atoms may be taken together with the carbon atoms to which they are attached to form a ring diradical selected from: 
R5 and R6 independently are hydrogen or C1-C6 alkyl, or R5 and R6 taken together with the nitrogen atom to which they are attached complete a 3- to 7-membered ring containing carbon atoms, the nitrogen atom, and optionally 1 heteroatom selected from O, S, and NR1, wherein R1 is as defined above;
is an integer of from 0 to 3;
m is an integer of from 0 to 6;
n is 0, 1, or 2;
Y is S, SO, or SO2; and
X is OH or NHOH.
Preferred compounds have Formula I wherein R4 is hydrogen or fluoro.
A preferred group of compounds have Formula II 
Wherein R1, R2, R3, n, p, and X are as defined above.
Especially preferred compounds have Formula II wherein R3 is halo, particularly bromo or iodo.
An especially preferred group of compounds have Formula I wherein R3 is alkyl substituted with amino, alkylamino, or dialkylamino. Illustrative examples include aminomethyl, 2-dimethylamino-ethyl, and 3-methylamino-butyl.
Further preferred compounds are those of Formula II, wherein two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a ring diradical selected from 
Further preferred compounds are those of Formulas I or II wherein X is OH.
Still further preferred compounds have Formulas I or II wherein X is NHOH.
Another embodiment of this invention is a pharmaceutical composition, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent. Preferred compositions comprise compounds of Formula II, or a pharmaceutically acceptable salt thereof.
Another embodiment of this invention is a method for inhibiting an MMP enzyme, comprising administering to a mammal an MMP enzyme inhibiting amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment of this invention is a method for treating a disease mediated by an MMP enzyme, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. Preferred methods comprise administering a compound having Formula II, or a pharmaceutically acceptable salt thereof.
A preferred method of treatment according to this invention is treatment of a disease selected from: cancer, especially breast carcinoma, inflammation, heart failure, osteoarthritis, and rheumatoid arthritis.
Another embodiment of the present invention is a compound of Formula III 
Or a pharmaceutically acceptable salt thereof,
wherein:
Each R1 and R2 independently are hydrogen or C1-C6 alkyl;
Z is (CH2)n;
each R3 and R4 independently are hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)m OH, (CH2)m OR5, (CH2)m cycloalkyl, (CH2)m aryl, (CH2)m substituted aryl, (CH2)m heteroaryl, (CH2)m substituted heteroaryl, (CH2)m carbocycle, (CH2)m heterocycle, (CH2)m NR5R6, (CH2)m COR5, (CH2)m CONR5R6, or (CH2)m CO2R5, NO2, phenoxy, CN, CHO;
or two R3 groups on adjacent carbon atoms may be taken together with the carbon atoms to which they are attached to form a ring diradical selected from: 
R5 and R6 independently are hydrogen or C1-C6 alkyl, or taken together with the nitrogen to which they are attached complete a 3- to 7-membered ring containing carbon atoms, the nitrogen atom, and optionally 1 heteroatom selected from O, S, and NR1, wherein R1 is as defined above;
p is an integer of from 0 to 3;
m is an integer of from 0 to 6;
n is 0, 1, or 2;
Y is S, SO, or SO2; and
X is OH or NHOH.
A preferred group of compounds have Formula IV 
Or a pharmaceutically acceptable salt thereof,
wherein:
Each R1 and R2 independently are hydrogen or C1-C6 alkyl;
each R3 independently is hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)m OH, (CH2)m OR5, (CH2)m cycloalkyl, (CH2)m aryl, (CH2)m substituted aryl, (CH2)m heteroaryl, (CH2)m substituted heteroaryl, (CH2)m carbocycle, (CH2)m heterocycle, (CH2)m NR5R6, (CH2)m COR5, (CH2)m CONR5R6, or (CH2)m C2R5, NO2, phenoxy, CN, CHO;
or two R3 groups on adjacent carbon atoms may be taken together with the carbon atoms to which they are attached to form a ring diradical selected from: 
R5 and R6 independently are hydrogen or C1-C6 alkyl, or taken together with the nitrogen to which they are attached complete a 3- to 7-membered ring containing carbon atoms, the nitrogen atom, and optionally 1 heteroatom selected from O, S, and NR1, wherein R1 is as defined above;
m is an integer of from 0 to 6;
p is an integer from 1 to 5;
n is 0, 1, or 2; and
X is OH or NHOH.
Especially preferred compounds have Formula III wherein R3 is halo, particularly chloro.
An especially preferred group of compounds have Formula III wherein R3 is alkyl substituted with amino, alkylamino, or dialkylamino. Illustrative examples include aminomethyl, 2-dimethylamino-ethyl, and 3-methylamino-butyl.
Further preferred compounds are those of Formulas III or IV wherein X is OH.
Still further preferred compounds have Formulas III or IV wherein X is NHOH.
Another embodiment of this invention is a pharmaceutical composition, comprising a compound of Formula III, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent. Preferred compositions comprise compounds of Formula IV, or a pharmaceutically acceptable salt thereof.
Another embodiment of this invention is a method for inhibiting an MMP enzyme, comprising administering to a mammal an MMP enzyme inhibiting amount of a compound of Formula III, or a pharmaceutically acceptable salt thereof.
Another embodiment of this invention is a method for treating a disease mediated by an MMP enzyme, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula III, or a pharmaceutically acceptable salt thereof. Preferred methods comprise administering a compound having Formula IV, or a pharmaceutically acceptable salt thereof.
A preferred embodiment of this invention is a method of treating a disease selected from: cancer, especially breast carcinoma, inflammation, heart failure, osteoarthritis, and rheumatoid arthritis, comprising administering to a mammal in need of treatment an effective amount of a compound selected from a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention is a method for treating a disease mediated by an MMP enzyme, comprising administering to a patient suffering from such a disease an effective amount of a combination of 2 or 3 compounds independently selected from Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
The compounds provided by this invention are those defined by Formula I. In Formula I, R1-R4 include xe2x80x9cC1-C6 alkylxe2x80x9d groups. These are straight and branched carbon chains having from 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, isopropyl, tert.-butyl, neopentyl, and n-hexyl. The alkyl groups can be substituted if desired, for instance with groups such as hydroxy, amino, alkylamino, and dialkylamino, halo, trifluoromethyl, carboxy, nitro, and cyano.
Examples of NR5R6 groups include amino, methyl amino, di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino, 3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl amino, and 3-carboxypropionyl amino. R5 and R6 can be taken together with the nitrogen to which they are attached to form a ring containing 3 to 7 carbon atoms and 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur. Examples of such cyclic NR5R6 groups include pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, pyridinyl, piperidinyl, pyrazinyl, morpholinyl, and the like.
xe2x80x9cHaloxe2x80x9d includes fluoro, chloro, bromo, and iodo.
xe2x80x9cAlkenylxe2x80x9d means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like.
xe2x80x9cAlkynylxe2x80x9d means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto, and the like. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed xe2x80x9cheterocyclylxe2x80x9d, which means a cycloalkyl group also bearing at least one heteroatom selected from O, S, or N R1, wherein R1 is as defined above, examples being oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine.
xe2x80x9cAlkoxyxe2x80x9d refers to the alkyl groups mentioned above bound through oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. In addition, alkoxy refers to polyethers such as xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94OH3, and the like.
xe2x80x9cAlkanoylxe2x80x9d groups are alkyl linked through a carbonyl, ie, C1-C5xe2x80x94C(O)xe2x80x94. Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl.
xe2x80x9cAcylxe2x80x9d means an R group that is an alkyl or aryl (Ar) group bonded through a carbonyl group, i.e., Rxe2x80x94C(O)xe2x80x94. For example, acyl includes a C1-C6 alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR5R6 or a carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl, and the like.
The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NR5R6, CONR5R6, COC1xe2x80x94C6 alkyl, phenyl, substituted phenyl, thio C1-C6 alkyl, C1-C6 alkoxy, hydroxy, carboxy, C1-C6 alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. xe2x80x9cSubstituted nitrogenxe2x80x9d means nitrogen bearing C1-C6 alkyl or (CH2)nPh where n is 1, 2, or 3. Perhalo and polyhalo substitution is also embraced.
Examples of substituted alkyl groups include 2-aminoethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl, and 2-(4-methylpiperazinyl)ethyl.
Examples of substituted alkynyl groups include 2-methoxyethynyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like.
Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
Further, examples of substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like.
The terms xe2x80x9cArxe2x80x9d and xe2x80x9carylxe2x80x9d refer to unsubstituted and substituted aromatic groups. Heteroaryl groups have from 4 to 9 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S, and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, morpholinyl, indolyl, benzotriazolyl, indazolyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thiophenyl, and the like.
Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groups independently selected from the group consisting of alkyl, alkoxy, thio, thioalkyl, halo, hydroxy, xe2x80x94COOR7, trifluoromethyl, nitro, amino of the formula xe2x80x94NR5R6, and T(CH2)mQR4 or T(CH2)mCO2R4 wherein m is 1 to 6, T is O, S, NR4, N(O)R4, NR4R6Y, or CR4R5, Q is O, S, NR5, N(O)R5, or NR5R6Y wherein R4 and R5 are as described above, and R7 is alkyl or substituted alkyl, for example, methyl, trichloroethyl, diphenylmethyl, and the like. The alkyl and alkoxy groups can be substituted as defined above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl, methoxy, chloro, methyl, NO2, phenoxy, CN, and CHO.
Two R3 groups on adjacent carbon atoms may be taken together with the carbon atoms to which they are attached to form a ring diradical selected from 
Examples 28, 33, and 36 below illustrate this embodiment.
The phrase xe2x80x9cLC purityxe2x80x9d means the percent amount of a compound in a sample being analyzed by high performance liquid chromatography.
The phrase xe2x80x9cMS APCIxe2x80x9d means the mass-to-charge value for a compound""s parent molecular ion, or for the compound""s parent molecular ion-hydrogen adduct as determined by positive ion atmospheric pressure chemical ionization mass spectrometry.
The term xe2x80x9cpatientxe2x80x9d means a mammal. Preferred patients include humans, cats, dogs, cows, horses, pigs, and sheep.
The term xe2x80x9canimalxe2x80x9d means a mammal. Preferred animals include humans, rats, mice, guinea pigs, rabbits, monkeys, cats, dogs, cows, horses, pigs, and sheep.
The term xe2x80x9ccancerxe2x80x9d as used herein includes all types of solid tumor diseases including colon cancer, breast cancer, lung cancer, prostate cancer, cancer of the oral cavity and pharynx, cancer of the stomach, small intestine, large intestine, rectum, liver, bone, connective tissue, skin, ovary, testis, bladder, kidney, brain, the central nervous system, and the like.
The phrases xe2x80x9ctherapeutically effective amountxe2x80x9d and xe2x80x9ceffective amountxe2x80x9d are synonymous unless otherwise indicated, and mean an amount of a compound of the present invention that is sufficient to improve the condition, disease, or disorder being treated. Determination of a therapeutically effective amount, as well as other factors related to effective administration of a compound of the present invention to a patient in need of treatment, including dosage forms, routes of administration, and frequency of dosing, may depend upon the particulars of the condition that is encountered, including the patient and condition being treated, the severity of the condition in a particular patient, the particular compound being employed, the particular route of administration being employed, the frequency of dosing, and the particular formulation being employed. Determination of a therapeutically effective treatment regimen for a patient is within the level of ordinary skill in the medical or veterinarian arts. In clinical use, an effective amount may be the amount that is recommended by the United States Food and Drug Administration, or an equivalent foreign agency.
The phrase xe2x80x9canticancer effective amountxe2x80x9d means an amount of invention compound, or a pharmaceutically acceptable salt thereof, sufficient to inhibit, halt, or cause regression of the cancer being treated in a particular patient or patient population. For example in humans or other mammals, an anticancer effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular cancer and patient being treated.
The phrase xe2x80x9cMMP enzyme inhibiting amountxe2x80x9d means an amount of invention compound, or a pharmaceutically acceptable salt thereof, sufficient to inhibit a matrix metalloproteinase enzyme, including a truncated form thereof, including a catalytic domain thereof, in a particular animal or animal population. For example in a human or other mammal, an MMP inhibiting amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular MMP enzyme and patient being treated.
It should be appreciated that the matrix metalloproteinases include the following enzymes:
MMP-1, also known as interstitial collagenase, collagenase-1, or fibroblast-type collagenase;
MMP-2, also known as gelatinase A or 72 kDa Type IV collagenase;
MMP-3, also known as stromelysin or stromelysin-1;
MMP-7, also known as matrilysin or PUMP-1;
MMP-8, also known as collagenase-2, neutrophil collagenase, or polymorphonuclear-type (xe2x80x9cPMN-typexe2x80x9d) collagenase;
MMP-9, also known as gelatinase B or 92 kDa Type IV collagenase;
MMP-10, also known as stromelysin-2;
MMP-11, also known as stromelysin-3;
MMP-12, also known as metalloelastase;
MMP-13, also known as collagenase-3;
MMP-14, also known as membrane-type (xe2x80x9cMTxe2x80x9d) 1-MMP or MT1-MMP;
MMP-15, also known as MT2-MMP;
MMP-16, also known as MT3-MMP;
MMP-17, also known as MT4-MMP;
MMP-18; and
MMP-19.
Other MMPs are known, including MMP-26, which is also known as matrilysin-2.
It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration, is within the level of ordinary skill in the pharmaceutical and medical arts, and is described below.
The term xe2x80x9cIC50xe2x80x9d means the concentration of test compound required to inhibit activity of a biological target, such as a receptor or enzyme, by 50%.
The phrase xe2x80x9ccatalytic domainxe2x80x9d means the domain containing a catalytic zinc cation of the MMP enzyme, wherein the MMP enzyme contains two or more domains. A catalytic domain includes truncated forms thereof that retain at least some of the catalytic activity of the MMP or MMP-CD. For example, the collagenases, of which MMP-1, MMP-8, and MMP-13 are members, have been reported to contain a signal peptide domain, a propeptide domain, a catalytic domain, and a hemopexin-like domain (Ye Qi-Zhuang, Hupe D., Johnson L., Current Medicinal Chemistry, 1996;3:407-418).
The phrase xe2x80x9ca method for inhibiting an MMP enzymexe2x80x9d includes methods of inhibiting a full-length MMP, truncated forms thereof that retain catalytic activity, including forms that contain the catalytic domain of the MMP, as well as the catalytic domain of the MMP alone, and truncated forms of the catalytic domain of the MMP that retain at least some catalytic activity.
It should be appreciated that it has been shown previously (Ye Qi-Zhuang, et al., supra., 1996) that inhibitor activity against a catalytic domain of an MMP is predictive of the inhibitor activity against the respective full-length enzyme.
The phrases xe2x80x9cpharmaceutical preparationxe2x80x9d and xe2x80x9cpreparationxe2x80x9d are synonymous unless otherwise indicated, and include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Pharmaceutical preparations are fully described below.
The phrase xe2x80x9cadmixedxe2x80x9d or xe2x80x9cin admixturexe2x80x9d means the ingredients so mixed comprise either a heterogeneous or homogeneous mixture. Preferred is a homogeneous mixture.
The compounds to be used in the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Some of the compounds may have chiral centers. The invention includes all racemates, pure enantiomers, and all geometric and positional isomers.
The compounds of Formula I, II, III, or IV are capable of further forming both pharmaceutically acceptable formulations comprising salts, including but not limited to acid addition and/or base salts, solvates and N-oxides of a compound of Formula I, II, III, or IV. This invention also provides pharmaceutical formulations comprising a compound of Formula I, II, III, or IV, together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. All of these forms can be used in the method of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I, II, III, or IV include salts derived form inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorus, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. of Pharmaceutical Science, 1977;66:1-19.
The acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine; see, for example, Berge, et al., supra.
The base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
The compounds of the present invention can be formulated and administered in a wide variety of oral and parenteral dosage forms, including transdermal and rectal administration. All that is required is that an MMP inhibitor be administered to a mammal suffering from a disease in an effective amount, which is that amount required to cause an improvement in the disease and/or the symptoms associated with such disease. It will be recognized to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I, II, III, or IV or a corresponding pharmaceutically acceptable salt or solvate of a compound of Formula I, II III, or IV.
The invention compounds are prepared by methods well known to those skilled in the art of organic chemistry. The compounds of Formula I are prepared utilizing commercially available starting materials, or reactants that are readily prepared by standard organic synthetic techniques. A typical synthesis of the invention compounds of Formula I is shown in Scheme 1 below, which illustrates the coupling of a biphenylsulfonyl halide to a suitably substituted thiomorpholine.
The first step in Scheme 1 comprises reacting a suitably substituted biphenylsulfonyl chloride (compound 1) with a thiomorpholine carboxylic acid ester (compound 2). The compounds are combined in approximately equimolar quantities in a mutual solvent such as pyridine or dioxane, and are stirred at a reduced temperature of about xe2x88x925xc2x0 C. to about 10xc2x0 C. The reaction is generally substantially complete within about 2 to about 10 hours. The product, a biphenylsulfonyl substituted thiomorpholine carboxylic acid ester (3), is isolated by diluting the reaction mixture with aqueous acid and extracting the product into an organic solvent such as ethyl acetate, chloroform, or dichloromethane. The product ester can be further purified, if desired, by standard methods such as chromatography, crystallization, distillation, and the like.
The biphenylsulfonyl-thiomorpholine carboxylic acid esters are readily hydrolyzed to the carboxylic acids (4) of Formula I by standard methods, for example by reaction with an acid such as trifluoroacetic acid in a solvent such as anisole or dimethylsulfoxide.
Scheme 1 further illustrates the synthesis of hydroxamic acids (5) of Formula I (Xxe2x95x90NHOH) by simply reacting the biphenyl sulfonyl-thiomorpholine carboxylic acid (4) with oxalyl chloride to give the corresponding acid chloride, and then reacting the acid chloride with hydroxylamine. The reaction generally is carried out in a mutual solvent such as tetrahydrofuran or dioxane, and is substantially complete within about 2 to 20 hours when carried out at a temperature of about 0xc2x0 C. to about 25xc2x0 C. The product hydroxamic acid (5) is readily isolated by extraction into an organic solvent such as diethyl ether or ethyl acetate, and concentration to dryness. The hydroxamic acids can be purified, if desired, by standard methods such as crystallization or chromatography over solid supports such as silica gel.
Scheme 1a illustrates the synthesis of sulfoxides and sulfones of Formula I (Yxe2x95x90SO or SO2). The biphenylsulfonyl-thiomorpholine carboxylic acid esters (3) are reacted with an oxidizing agent such as peracetic acid or m-chloroperbenzoic acid. Reaction of the ester with one equivalent of oxidizing agent provides the invention sulfoxides (Yxe2x95x90SO), and reaction with two equivalents or more effects complete oxidation to the corresponding sulfones (Yxe2x95x90SO2) (6).
As shown in Scheme 1a and discussed above, the carboxylic acid esters (of either a thiomorpholine sulfoxide or sulfone) (e.g., 6) is readily hydrolyzed to the carboxylic acids of Formula I (7), which are potent MMP inhibitors, and which can be readily converted to the invention hydroxamic acids (8). 
Scheme 2 illustrates an alternative synthesis of the biphenyl invention compounds wherein a thiomorpholine is condensed with a phenylsulfonyl chloride, wherein the phenyl bears a good leaving group xe2x80x9cLxe2x80x9d as a substituent. Good leaving groups are halogens such as bromo and iodo. A preferred reactant is pipsyl chloride (4-iodobenzenesulfonyl chloride). The condensation is carried out in a manner analogous to that described above for the biphenyl series, and the product is an xe2x80x9cLxe2x80x9d substituted phenylsulfonyl-thiomorpholine carboxylic acid ester (10). The leaving group xe2x80x9cLxe2x80x9d is readily displaced by reaction with any R3 substituted phenyl boronic acid compound to provide the corresponding R3 substituted biphenylsulfonyl-thiomorpholine carboxylic acid ester (3). The displacement reaction is accomplished by reacting the xe2x80x9cLxe2x80x9d substituted phenylsulfonyl thiomorpholine with an equimolar quantity, or slight excess, of the benzene boronic acid in a mutual solvent such as dioxane. The reaction is generally carried out at an elevated temperature of about 60xc2x0 C. to 90xc2x0 C., and generally is complete within 4 to 12 hours. The product (3) is isolated by removing excess solvents and extraction into an organic solvent such as ethyl acetate or diethyl ether. The product can be further purified by chromatography, crystallization or the like. The thiomorpholine carboxylic acid esters (3) are readily hydrolyzed to the free acids (4) by the methods described above, and the carboxylic acids can be converted to the corresponding hydroxamic acids by standard methods. 
Scheme 3 illustrates derivatization on the terminal phenyl ring of the biphenylsulfonyl-thiomorpholine carboxylic acids where R3 is a hydroxymethyl group. The hydroxymethyl group readily reacts with methanesulfonyl chloride (MSCl) to provide the corresponding methanesulfonyloxy methyl substituted biphenyl analog. The methanesulfonyloxy methyl substituted biphenyl analog group is a good leaving group (L) and is readily displaced by nucleophiles such as amines (HNR5R6) to provide the corresponding aminoalkyl substituted biphenyl invention compound (12). These compounds can be further hydrolyzed to the free acids (13), which can be converted to the hydroxamic acids, all as described above. 
The invention compounds of Formula I are ideally suited to synthesis by general combinatorial methodologies. Schemes 4 and 5 illustrate the use of resin supports to facilitate the synthesis of invention compounds. As shown in Scheme 4, a phenylsulfonyl-thiomorpholine carboxylic acid (14) bearing a good leaving group (Lxe2x95x90I) on the phenyl ring is reacted with a hydroxyl amine that is attached to a solid resin (e.g., a polystyrene resin xe2x80x9cPSxe2x80x9d) through the oxygen atom to provide a phenylsulfonyl-thiomorpholine hydroxamic acid (15) bound to a resin support (PS). The leaving group (Lxe2x95x90I) is displaced by reaction with a suitably substituted phenyl boronic acid by the general process described above. The biphenyl analog (16) that is produced is next liberated from the resin support (PS) by reaction with an acid such as trifluoroacetic acid to give the corresponding hydroxamic acid of the invention (5).
Scheme 5 illustrates that the biphenylsulfonyl-thiomorpholine hydroxamic acid-resin complex (16) can be further modified to provide the aminoalkyl substituted biphenyl thiomorpholine hydroxamic acids of the invention (19). 
It should be appreciated that compounds of Formula III may be readily prepared by adapting the procedures illustrated in Schemes 2 and 4, wherein the phenylboronic acid intermediates used in the second steps are replaced with thiopheneboronic acid intermediates of formula (A) 
Wherein R3 is as defined above for Formula III.
It may be desirable to derivatize certain reactive functional groups during chemical reactions in order to avoid unwanted side reactions. Groups such as carboxylic acids, amines and hydroxy groups generally are protected with any of a number of common protecting groups that can be readily removed when desired. The use of protecting groups in organic synthesis is fully described by Greene and Wuts in Protecting Groups in Organic Synthesis, (John Wiley and Son Press, 2nd edition), which is incorporated herein by reference. Typical amino acid hydroxy protecting groups include acyl groups such as formyl, acetyl, and benzoyl. Typical protecting groups for carboxylic acids include ester-forming groups such as tert-butyl, 2,2,2-trichloroethyl, and benzyl. Other common protecting groups include tert-butoxycarbonyl (BOC) and trimethylsilyl.
The following detailed examples further illustrate the synthesis of typical invention compounds of Formula I and Formula III. The examples are representative only, and are not to be construed as limiting the invention in any respect. All references cited herein are incorporated by reference.